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PubMed · 40480020

Epigenetic mechanisms underlying variation of IL-6, a well-established inflammation biomarker and risk factor for cardiovascular disease.

Jessica I Lundin·Ulrike Peters·Yao Hu·Farah Ammous·Emelia J Benjamin·Joshua C Bis·Jennifer A Brody·Mary Cushman·Harriett Fuller·Chris Gignoux·Xiuqing Guo·Jeff Haessler·Chris Haiman·Roby Joehanes·Silva Kasela·Eimear Kenny·Tuuli Lappalainen·Daniel Levy·Chunyu Liu·Yongmei Liu·Ruth J F Loos·Tara Matise·Kari E North·Sungshim L Park·Scott M Ratliff·Alex Reiner·Stephen S Rich·Jerome I Rotter·Jennifer A Smith·Nona Sotoodehnia·Russell Tracy·David Van den Berg·Ting Ye·Wei Zhao·Laura M Raffield·Charles Kooperberg·PAGE Study
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Abstract

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, yet the underlying molecular mechanisms remain less understood. Chronic low-grade inflammation is a complex immune response contributing to the pathophysiology of cardiovascular disease. This response is signaled in part by interleukin-6 (IL-6), a pleiotropic, pro-inflammatory cytokine. Phenotypic variance in circulating IL-6 level may be explained in part by DNA methylation which is increasingly being associated with cardiovascular effects. METHODS: In this study we evaluated methylated DNA (CpG sites) associated with blood IL-6 levels across &#x223c;4,400 ancestrally diverse individuals (81&#xa0;% self-reported White; 9&#xa0;% Black or African American, 8&#xa0;% Hispanic or Latino/a, and 2&#xa0;% Chinese American). RESULTS: We identified 178 CpG sites associated with IL-6 (p<0.05/&#x223c;395,000). Among the sites, cg04437762 is located within the transcription unit of IL6R, a current therapeutic target for inflammatory disease, and cg26692003 and cg00464927 were significant for IL6 and IL6ST trans-CpG-gene transcripts. Functional gene expression downstream of methylation identified cellular response to IL-6 and B-cell regulation and activation pathways. Four genes were linked with both a genetic component of cardiovascular disease and an IL-6 associated CpG site. Three CpG sites identified through Mendelian randomization analyses supported inference of a causal effect on IL-6 levels, including the LYN gene that regulates immune cell signaling and has been previously associated with atherosclerosis. CONCLUSIONS: Overall, we identified several novel IL-6-CpG sites and downstream pathways affected by methylation. Follow-up functional studies including the regulation of IL-6 would complement current knowledge of CVD pathophysiology and potential therapeutic targets.

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HumansInterleukin-6Cardiovascular DiseasesEpigenesis, GeneticDNA MethylationMaleInflammationFemaleCpG IslandsBiomarkersMiddle AgedRisk FactorsReceptors, Interleukin-6Genetic Predisposition to DiseaseHeart Disease Risk FactorsCytokine Receptor gp130Journal ArticleResearch Support, N.I.H., Extramural

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Jessica I Lundin, Ulrike Peters, Yao Hu, Farah Ammous, Emelia J Benjamin, Joshua C Bis, Jennifer A Brody, Mary Cushman, Harriett Fuller, Chris Gignoux, Xiuqing Guo, Jeff Haessler, Chris Haiman, Roby Joehanes, Silva Kasela, Eimear Kenny, Tuuli Lappalainen, Daniel Levy, Chunyu Liu, Yongmei Liu, Ruth J F Loos, Tara Matise, Kari E North, Sungshim L Park, Scott M Ratliff, Alex Reiner, Stephen S Rich, Jerome I Rotter, Jennifer A Smith, Nona Sotoodehnia, Russell Tracy, David Van den Berg, Ting Ye, Wei Zhao, Laura M Raffield, Charles Kooperberg, PAGE Study. 2025-05-20. Epigenetic mechanisms underlying variation of IL-6, a well-established inflammation biomarker and risk factor for cardiovascular disease.. https://doi.org/10.1016/j.atherosclerosis.2025.120219

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